title: Endotoxin exposure, CD14 and wheeze among farmers: a gene--environment interaction.
abstract: OBJECTIVE
  Endotoxin-exposed workers are at an increased risk of non-atopic asthma and lung-function decline. Genetic variants may influence susceptibility to these effects. The objective of the present study was to assess whether the association between occupational endotoxin exposure and wheeze is modified by innate immunity gene variants.
  
  
  METHODS
  Twenty-four single nucleotide polymorphisms (SNPs) in CD14, Toll-like receptor 4 (TLR4), TLR2, MD2 and MyD88 were genotyped in 408 agricultural workers with spirometry and questionnaire data on asthma symptoms available. Personal airborne endotoxin exposure levels were estimated in 249 exposure measurements.
  
  
  RESULTS
  The association between endotoxin exposure and wheeze was modified by three CD14 SNPs: -260 C/T (rs2569190), -1247 T/C (rs2569191) and -1721 A/G (rs2915863), and one MD2 SNP (rs10808798 T/C). In individuals carrying the CD14 and MD2 major allele variants, the prevalence of wheeze increased with increasing endotoxin concentration, whereas this was the opposite in minor allele homozygotes. Interaction between endotoxin exposure and genotype was statistically significant under the best-fitting recessive model (p=0.05 to 0.006). Correction for multiple comparisons resulted in marginally significant p values for interaction (p<0.06) for CD14 -260 C/T and -1247 T/C, and for MD2 rs10808798 T/C. The CD14 SNPs appeared to modify associations between endotoxin exposure and forced expiratory volume in 1 s in a similar direction (p interaction=0.07 to 0.15).
  
  
  CONCLUSIONS
  The association between occupational endotoxin exposure and wheeze in agricultural workers was significantly modified by genetic variants in CD14 and MD2. Our study suggests that carriers of the functional CD14/-260 C allele are more responsive to endotoxin exposure than T allele homozygotes.
authors.affiliation: Institute for Risk Assessment Sciences, Division Environmental Epidemiology, PO Box 80178, 3508 TD Utrecht, The Netherlands. l.a.smit@uu.nl
authors.forename: Lidwien A M
authors.initials: LA
authors.lastname: Smit
authors.forename: Dick
authors.initials: D
authors.lastname: Heederik
authors.forename: Gert
authors.initials: G
authors.lastname: Doekes
authors.forename: Gerard H
authors.initials: GH
authors.lastname: Koppelman
authors.forename: Renske W B
authors.initials: RW
authors.lastname: Bottema
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.forename: Inge M
authors.initials: IM
authors.lastname: Wouters
mesh_terms: D000328:Adult; D000383:Agriculture; D004731:Endotoxins / Q000633:toxicity*; D005260:Female; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology; D051218:Lymphocyte Antigen 96 / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D009784:Occupational Diseases / Q000209:etiology / Q000235:genetics; D016273:Occupational Exposure / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D012135:Respiratory Sounds / Q000209:etiology* / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology
chemical_list: D004731:Endotoxins; C495377:LY96 protein, human; D018950:Lipopolysaccharide Receptors; D051218:Lymphocyte Antigen 96; D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4